The process of bone modeling and remodeling plays an important role in development, growth and metabolism of bone. Bone modeling initiates from birth and then continues until adolescence/manhood at which time the skeleton matures to an end of growth of an individual, thus achieving the peak bone mass from between his/her twenties to early-thirties. Since then, a bone remodeling process involving removal and replacement of bone is repeated for about 3 years, during which bone formation and bone resorption are coupled to maintain the balance therebetween. After this period of time, bone formation cannot sufficiently keep up with bone loss occurring due to bone resorption, which eventually results in an about 0.3 to 0.5% annual decrease in bone mass. In particular, women will undergo a significant bone loss of 2 to 3% yearly at the early stage of menopause.
Bone consists mainly of four cell types, namely, osteoblasts, osteoclasts, lining cells and osteocytes. Here, osteoblasts, which are derived from bone marrow stromal cells, are differentiated cells of synthesizing a bone matrix and play a leading part in bone formation, whereas osteoclasts, which are derived from hematopoietic stem cells, play a leading part in bone resorption.
Osteoporosis is a condition in which a calcified bone tissue density is decreased and thus the compact substance of bone is lost gradually, leading to broadening of the marrow cavity. As osteoporosis progresses, bone becomes fragile and consequently bone fractures may readily occur even with a small impact. Bone mass is affected by a variety of factors including genetics, nutrition, hormonal changes, physical exercise and lifestyle habits. Aging, insufficient exercise, being underweight, smoking, low-calcium dietary intake, menopause and ovariectomy are known as pathogenic causes of osteoporosis. Although there is a difference among individuals, it is known that black people exhibit a lower bone resorption level than white people, thus meaning that black people have a higher bone mass. The peak bone mass is generally observed between age 14 and 18, and then the bone mass decreases with aging at a rate of about 1% per year. In particular, bone is continuously decreased from the age of 30 in women and is rapidly reduced due to hormonal changes after menopause. In other words, when reaching the perimenopausal period, a level of estrogen is rapidly decreased. At this time, large numbers of B-lymphocytes are formed as if it happened by interleukin-7 (IL-7), and pre-B cells are accumulated in bone marrow, which consequently leads to an increase in the level of IL-6, thus resulting in an increased activity of osteoclasts and finally a decreased level of bone mass.
As described above, osteoporosis, although showing a difference in terms of disease severity to a certain extent, is inevitable in the aged, especially in post-menopausal women, so osteoporosis and its therapeutic agents have increasingly become the center of interest as the aging population grows in advanced countries. The treatment of bone diseases forms an approximately 130 billion dollar-market throughout the world, which is assumed to grow further. Thus, numbers of worldwide research institutions and pharmaceutical companies have invested heavily in development of therapeutic agents for the treatment of bone diseases. Also recently in Korea, the morbidity of osteoporosis has begun to rapidly soar as the average span of human life comes close to 80 years. According to research recently conducted for local residents, when the research results are normalized in terms of total population, it has been reported that 4.5% of males have osteoporosis and 19.8% of females suffer from the same disease. These results suggest that osteoporosis is a more common disease than diabetes or cardiovascular diseases and when considering the suffering of patients due to fractures or when estimating costs incurred for the treatment of a disease, osteoporosis is a very important public health problem.
Many kinds of substances have been developed hitherto as anti-osteoporosis agents. Among those therapeutic substances, estrogen, which is most commonly used as an anti-osteoporosis agent but whose practical efficacy has not yet been demonstrated, disadvantageously requires life-time administration, and long-term administration thereof may result in adverse side effects such as increased risk of breast cancer or uterine cancer. Alendronate also has problems associated with indefinite understanding of medicinal efficacy, sluggish gastrointestinal absorption, and pathogenesis of inflammation on gastrointestinal and esophageal mucosa. Calcium preparations are known to exhibit superior therapeutic effects with lower adverse side effects but are limited to prevention rather than treatment. Incidentally, vitamin D preparations, such as calcitonin, are known, but efficacy and adverse side effects thereof have not yet been sufficiently investigated. To this end, there is a need for the development of a novel therapeutic agent for the treatment of metabolic bone diseases which exhibits excellent therapeutic effects and a low rate of adverse side effects.
Meanwhile, studies have recently been reported showing that reactive oxygen species (ROS) generated due to oxidative stress are involved in metabolism of bone (Darden, A. G., et al., J. Bone Miner, Res., 11:671-675, 1996; Yang, S., et al., J. Biol. Chem., 276:5452-5458, 2001; Fraser, J. H., et al., Bone 19:223-226, 1996; and Yang, S., et al., Calcif. Tissue Int., 63:346-350, 1998). Further, it is known that bone remodeling is carried out through the relative action between bone-forming osteoblasts and bone-resorbing osteoclasts (OC). Multinuclear osteoclasts are differentiated from a monocyte/macrophage lineage of hematopoietic progenitor cells through a multi-stage process of cell adhesion, proliferation, motility, cell-cell contact and terminal fusion for the formation of multinucleated giant cells. This process is initiated by binding of a receptor activator of nuclear factor-kB ligand (hereinafter, referred to as “RANKL”) to a receptor activator of nuclear factor-kB ligand (hereinafter, referred to as “RANK”) and is then transmitted through the activation of several signaling cascades. The activated signaling pathway includes NF-KB, extracellular signal-regulated kinase (hereinafter, referred to as “ERK”), c-Jun N-terminal kinase (hereinafter, referred to as “JNK”) and p38 mitogen-activated protein (MAP) kinase through a tumor necrosis factor (TNF) receptor-associated factor 6 (hereinafter, referred to as “TRAF6”). Such a signaling event has a direct effect on the modulation of differentiation and action of osteoclasts (Boyle, N. J., et al., Nature, 423:337-342, 2003). Once osteoclasts are differentiated, the resorption of bone is accelerated by ROS generated due to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. An NADPH oxidase inhibitor leads to a reduction of ROS and bone resorption (Yang, S., et al., Calcif. Tissue Int., 63:346-350, 1998). These results are consistent with the theory suggesting that the generation of ROS in osteoclasts is dependent on the activity of NADPH oxidase and is directly connected with the function of osteoclasts.
Therefore, the inventors of the present application have conducted extensive and intensive studies based on the idea that an anti-osteoporosis agent may be developed by taking advantage of a molecular mechanism which inhibits the activity of RANKL and found that pyrazole derivatives of the present invention exhibit excellent NADPH oxidase inhibitory activity and these compounds may be used for the prevention or treatment of osteoporosis. The present invention has been completed based on these findings.